INHIBITION OF BETA-AMYLOID FORMATION IDENTIFIES PROTEOLYTIC PRECURSORS AND SUBCELLULAR SITE OF CATABOLISM

Cerebral deposition of beta-amyloid protein isa pathological feature c entral to Alzheimer's disease. Production of beta-amyloid by proteolyt ic processing of the beta-amyloid precursor protein (beta APP) is a cr itical initial step in beta-amyloidogenesis. We use an inhibitor of be ta APP processing to block beta-amyloid peptide formation. Application of the inhibitor to cultured cells results in an accumulation of prot eolytic intermediates of beta APP, enabling a precursor-product relati onship between beta APP carboxy-terminal fragments and beta-amyloid pe ptides to be demonstrated directly. In the presence of inhibitor, thes e amyloidogenic carboxy-terminal fragments can be degraded to nonamylo idogenic products. The catabolism of beta APP carboxy-terminal interme diates and the formation of beta-amyloid peptides ate likely to involv e an early endosomal compartment as the subcellular site of processing .